Re-obstruction (re-stenosis) of arteries after mechanical or surgical interventions to improve blood flow is a major problem. For example, after coronary angioplasty, re-stenosis rates of 30-40% have been reported. Re-stenosis after surgery to relieve carotid obstructions also occurs, and re-stenosis can occur in other vessels as well. Current treatments for re-stenosis include drugs, such as aspirin or lovastatin, that may somewhat reduce the incidence of restenosis; and the placement of mechanical stents in the vessel lumen to attempt to hold the vessel open. Nevertheless, these methods are at best only partially effective and are often invasive. There exists a need for a simple, effective, non-invasive or minimally invasive approach to reduce re-stenosis or slow its development in patients who undergo mechanical or surgical revascularization procedures.
The process of re-stenosis involves, in part, the proliferation of cells in the arterial wall in response to injury during the revasculariation procedure. There is a role for cholesterol and possibly other lipids in this process: high plasma concentrations of LDL and apolipoprotein B, the major protein of atherogenic lipoproteins, are associated with increased carotid re-stenosis (Colyvas et al. Circulation 85:1286-1292, 1992), and lovastatin, a cholesterol synthesis inhibitor, somewhat reduces coronary re-stenosis (Sahni et al Am. Heart J. 121 [6 pt 1]: 1600-1608, 1996). There exists a need for better methods, devices, and modes of operation of devices to manipulate the lipid content and composition of the arterial wall before, during, and after revascularization procedures, to reduce re-stenosis. Small LDL size has also been associated with increased re-stenosis (Colyvas 1992), and so there exists a need for methods to change LDL composition and size.
The intravenous administration of cholesterol-poor phospholipid vesicles (liposomes) or other particles to transport cholesterol and other exchangeable material from lipoproteins and peripheral tissues, including atherosclerotic arterial lesions, to the liver produces substantial derangements in hepatic cholesterol homeostasis, such as enhanced hepatic secretion of apolipoprotein-B, and suppression of hepatic LDL receptors. The hepatic derangements lead to increased plasma concentrations of LDL and other atherogenic lipoproteins. Increased concentrations of LDL or other atherogenic lipoproteins will accelerate, not retard, the development of vascular complications. Deranged hepatic cholesterol homeostasis can also be manifested by abnormal regulation of other genes, such as a gene for the LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha hydroxylase, and a gene regulating a function involved in cholesterol homeostasis. There exists a need for methods or compounds that can produce a removal of cholesterol and other exchangeable material from peripheral cells, tissues, organs, and extracellular regions, but without harmfully disrupting hepatic cholesterol homeostasis.
In general, several human conditions are characterized by distinctive lipid compositions of tissues, cells, or membranes. For example, in atherosclerosis, cholesterol (unesterified, esterified, and oxidized forms) and other lipids accumulate in cells and in extracellular areas of the arterial wall and elsewhere. These lipids have potentially harmful biologic effects, for example, by changing cellular functions and by narrowing the vessel lumen, obstructing the flow of blood. Removal of these lipids would provide numerous, substantial benefits. In aging, cells have been shown to accumulate sphingomyelin and cholesterol, which alter cellular functions. These functions can be restored in vitro by removal of these lipids and replacement with phospholipid from liposomes. A major obstacle to performing similar lipid alterations in vivo has been disposition of the lipids mobilized from tissues, cells, extracellular areas, and membranes. Natural (e.g., high-density lipoproteins) and synthetic (e.g., small liposomes) particles that could mobilize peripheral tissue lipids have a substantial disadvantage: they deliver their lipids to the liver in a manner that disturbs hepatic cholesterol homeostasis, resulting in elevations in plasma concentrations of harmful lipoproteins, such as low-density lipoprotein (LDL), a major atherogenic lipoprotein.
The invention described herein provides methods and compositions related the removal of cholesterol and other lipids from peripheral tissues, and otherwise altering peripheral tissue lipids, in patients undergoing revascularization procedures, while controlling plasma concentrations of LDL and other atherogenic lipoproteins and avoiding harmful disruption of hepatic cholesterol homeostasis.
This invention methods and compositions that related to the "reverse" transport of lipids and other exchangeable material from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations. There exists a need for a method of, treatment, and a pharmaceutical composition for forcing the reverse transport of lipids from peripheral tissues to the liver in vivo while controlling plasma LDL concentrations; of regulating hepatic parenchymal cell cholesterol content and metabolism in a cell having at least one gene selected from the group consisting of a gene for an LDL receptor, a gene for HMG-CoA reductase, a gene for cholesterol 7-alpha-hydroxylase, and a gene regulating a function involved in cholesterol homeostasis; and, homeostasis thereof; suppressing hepatic expression of a cholesterol ester transfer protein gene in vivo, whereby plasma LDL and HDL are controlled as a result of said administration; suppressing the rise in plasma LDL concentrations after administration of an agent having small acceptors of cholesterol or other lipids; of diagnosing a side-effect of reverse transport of cholesterol from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period, whereby a side effect of administration of said liposomes is diagnosed and effectively regulated; and, diagnosing and treating a side-effect of reverse transport of lipids from peripheral tissues to the liver in vivo accompanying parenteral administration of a multiplicity of large liposomes and small liposomes during a treatment period. There further exists a need for a system in which patients will have a decreased risk of developing atherosclerosis and/or cellular changes from aging; an improved method of reducing the lipid content of lesions. Other needs and solutions to these needs will be revealed further herein.
The present invention addresses these needs so that diseases and detrimental medical conditions can be treated, controlled or eliminated. The present invention targets a market of millions of individuals world-wide who suffer from medical conditions the present invention is directed to solving. It is an object of the invention to solve the problems enumerated above.